Mutational Dynamics of SARS-CoV-2 in Austria

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As a leading biomedical research institute, CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, is committed to advancing our molecular understanding of the COVID-19 pandemic and the causative pathogen, SARS-CoV-2. Biomedical research on the virus and the disease will contribute substantially to informed policy decisions and, ultimately, the development of new treatments.

An interdisciplinary team at CeMM under the project leadership of virologist Andreas Bergthaler and computational biologist Christoph Bock will investigate SARS-CoV-2 genome evolution in patients by deep sequencing and sophisticated computational analyses. This will result in rapid open sharing of SARS-CoV-2 genomes from Austria, inform epidemiologists to reconstruct transmission chains, and offer invaluable insights into the molecular dynamics of the ravaging viral pandemic.

The work is part of a collaboration network with Elisabeth Puchhammer-Stöckl from the Center for Virology of the Medical University of Vienna as primary partner. The network is open to additional collaborations and especially welcomes contributions from clinical virologists and diagnostics laboratories across Austria. First collaborations with evolution biologists, population geneticists and virologists have already started. Integration of Austria’s contribution into an emerging world-wide map of SARS-CoV-2 mutations will help decipher the mutational dynamics underlying the pandemic.

“CeMM is focusing efforts to soon openly share the first SARS-CoV-2 genomes from Austria with the world. We encourage the scientific community and industry to use these results to accelerate research to fight the coronavirus, and hope the data will support policy makers and epidemiologists to better understand how the virus is spreading”, says Giulio Superti-Furga, CeMM Director.

CeMM events and seminars postponed

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Due to the latest developments in the corona virus (COVID-19) and as a preventive health measure, CeMM has decided to cancel all public events and seminars until 13 April 2020. Events will be rescheduled to a later date.

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Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have studied how Solute Carriers (SLCs), a large family of membrane transport proteins, influence the activity and potency of cytotoxic drugs, such as those used in the treatment of leukemia and other cancers. Their study, published in the journal Nature Chemical Biology, uncovers the dependency of most drugs studied on the function of at least one SLC. In some cases, the drug required the transporter to enter into the cell, in other cases, it provided small molecules (metabolites), which are crucial to the drug’s activity or the cell response to it. These findings shed new light onto the biological roles of transporters and open the path to the development of future precision therapies.

Solute carriers (SLCs) represent the largest family of transmembrane transporters in the human genome, with over 400 members arranged into 65 families. They have a key role in determining cellular metabolism and control essential physiological functions, including nutrient uptake, ion transport and waste removal. SLCs are vital for maintaining a stable internal state of the human body (known as homeostasis), but the presence of genetic variation (polymorphisms) in SLCs are associated with several diseases, such as gout or diabetes, while gene mutations are associated with literally hundreds of disorders including many metabolic deficiencies and orphan diseases.

Solute carriers have been shown to act as drug targets, as well as constitute paths for drug absorption into specific organs. However, despite of decades of studies, there is still a lack of systematic surveys of transporter-drug relationships in human cells. Uncovering how particular drugs enter human cells and how the cell metabolism affects them is key to gaining a better understanding of the side effects and limitations of current drugs and thus developing more effective drug therapies in the future.

Expanding on a previous study (Winter et al. Nat Chem Biol, 10, pp 768-773, 2014), which uncovered how a single solute carrier (SLC35F2) is necessary in the uptake of the cytotoxic compound YM-155, Giulio Superti-Furga and his group at CeMM now performed a more systematic investigation on the role of solute carriers in determining the activity of a large and diverse set of cytotoxic compounds. Their goal was to survey on the “how often” and “how” SLC transporters would lose or a affect the activity of a certain drug.

In their study, CeMM researchers built a CRISPR/Cas9-focused library specifically targeting 394 solute carriers and applied it to identify SLCs affecting the activity of a panel of 60 chemically diverse, most of them clinically approved, cytotoxic compounds. They determined that approximately 80% of the screened drug set shows a dependency with at least one solute carrier. To further validate these results, the scientists individually validated a subset of SLC-drug interactions and employed uptake assays and transcriptomics approaches to investigate how some of the SLCs affected drug uptake and activity. “The use of a custom-made, SLC-focused library was instrumental in allowing us to screen a large number of compounds, revealing hundreds of SLC-drug associations and providing many novel insights into SLC biology and drug mechanisms”, says Enrico Girardi, CeMM senior postdoctoral fellow and first author of the study.

The present study is the result of a cross-disciplinary collaboration with researchers from the University of Vienna Pharmacoinformatics Research Group of Gerhard Ecker as well as the group of Stefan Kubicek at CeMM. It provides not only a strong validated argument to demonstrate the requirement of solute carriers in cellular uptake and drug’s activity, but also an experimentally validated set of SLC-drug associations for several clinically relevant compounds. The evidence provided by CeMM researchers opens the pathway to further investigations of the genetic determinants of drug activity and especially uptake in human cells. “This study raises strong doubts that the generally accepted idea that most drugs can enter cells by simply diffusing through its membrane is correct and highlights the increasingly appreciated need to systematically studying the biological roles of solute carriers”, says Giulio Superti-Furga, CeMM Scientific Director and last author of the study. Gaining further insights into how the transporters affect the uptake and activity of drugs in tumors and tissues allows scientists to predict and counteract resistance mechanisms to design the most effective precision therapies. Furthermore, understanding the relationship between the expression of SLCs, cellular/organismal metabolism and nutrition is likely to allow the opening of novel therapeutic avenues in the future.

The study “A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs” was published in Nature Chemical Biology on 9 March 2020. DOI: 10.1038/s41589-020-0483-3

Funding:The study was funded with support by the Austrian Academy of Sciences, the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 695214, awarded to Giulio Superti-Furga), the Austrian Science Fund (FWF I2192-B22 ERASE; FWF P29250-B30 VITRA) and by a Marie Sklodowska-Curie fellowship to Enrico Girardi (MSCA-IF-2014-661491).Research in the Kubicek laboratory is supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF) F4701 and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437).The Pharmacoinformatics Research Group (Ecker lab) acknowledges funding provided by the Austrian Science Fund FWF AW012321 MolTag.

March 06, 2020

AustroVirology Symposium 2020

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On 5 March 2020, the first AustroVirology Symposium took place at the St. Anna Kinderkrebsforschung (CCRI) in Vienna. The event, organized by CeMM PI Andreas Bergthaler and Karin Kosulin (CCRI), brought together 75 virologists from 12 institutions across Austria. The goal was to capture the rich diversity of academic, clinical and industrial virological research and to provide a platform to meet colleagues and forge new collaborations in the field.

The symposium kicked off by an inspiring keynote lecture about the co-evolution of phages and bacteria by Martin Polz, Professor at the Massachusetts Institute of Technology (MIT) and the Universität Wien. The programme included 10 short talks which covered diverse subdisciplines of virology, including structural biology, immunology, organoids, clinical diseases and biotechnological applications. Finally, the event was concluded with an open discussion and a poster session with additional networking opportunities.

The successful AustroVirology Symposium gave a vibrant demonstration of the existing excellent virus research in Austria and fostered intense networking. Considering the current SARS-CoV2 epidemics and COVID-19, the virology research community continues to play an ever-important role for our understanding of basic biology, the fight of infectious diseases and the development of novel solutions such as innovative vaccines.

February 29, 2020

Rare Disease Day 2020

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Today is Rare Diseases Day, which takes place every four years on 29 February. Currently 400 million people worldwide, of whom 30 million are in Europe[i] and 400,000 in Austria, are affected by a rare disease. There are between 5,000 and 8,000 different rare diseases[ii], and the vast majority are caused by a single genetic defect, which can already be detected in early childhood. They are not as uncommon as we may think but they are so little widespread that those who are affected by them are often not properly diagnosed or do not receive the most appropriate treatment for their condition.

Developing more effective and appropriate treatments requires a lot of research. Kaan Boztug, CeMM Adjunct PI, Scientific Director of St. Anna Children's Cancer Research (CCRI) and Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) in Vienna is a leading expert in primary immunodeficiency and hematological malignancies and dedicated to this goal. His research group successfully works on understanding some of the molecular processes that control immune homeostasis and autoimmunity using model diseases and state-of-the art genomic approaches with the aim to enable the use of tailored treatment strategies. In his interview with Wolfgang Däuble for the Austrian newspaper “Die Presse”, Kaan Boztug gives more details about serious chronic diseases, explains why it is so important to invest in rare disease research and how this led to the founding of LBI-RUD.

The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was launched by the Ludwig Boltzmann Gesellschaft in April 2016 together with its partner institutions CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, the Medical University of Vienna, and the St. Anna Children’s Cancer Research Institute (CCRI). Its research remit is the thorough analysis of rare diseases of the hematopoietic system, the immune system and the nervous system – as such not only dedicated to provide research for the development of personalized therapeutics for affected patients, but with similar efforts dedicated to unravel novel insights into human biology. Benefitting from access to the infrastructure and know-how of its partner institutions, LBI-RUD has established a coordinated research programme, integrating and considering scientific, sociologic, ethical and economical aspects of rare diseases.

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Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases in Vienna, the University Medical Center of Regensburg, and the National Institute of Hematology and Infectious Diseases and the Semmelweis University in Budapest have studied the response to targeted leukemia therapy in unprecedented detail, using single-cell sequencing and epigenetic analysis. The paper published in the journal Nature Communications uncovers a precise molecular program in patients with chronic lymphocytic leukemia (CLL) who start treatment with the targeted cancer drug ibrutinib. While this program was shared by all patients, the speed of its execution differed widely. These results will help develop personalized strategies for managing CLL as a chronic disease, which is particularly relevant for CLL as a disease of the elderly.

Chronic lymphocytic leukemia (CLL) is the most common form of blood cancer (leukemia) in the Western world, affecting approximately 1.2% of all cancer patients. This type of cancer starts with the lymphocytes (a type of white blood cells) that are produced in the bone marrow. CLL is characterized by the proliferation of abnormal lymphocytes (B cells) that fail to mature and grow out of control. These abnormal cells accumulate in the bone marrow and lymph nodes, taking the place of other healthy cell types and impeding their normal development. Finding the most suitable therapy for each patient poses a challenge due to the clinical and molecular heterogeneity of this disease, with some patients facing slow disease progression, whereas others face rapid progression and require quick medical response.

The cancer drug ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has remarkable efficacy in most patients with CLL. It is becoming the standard of care for most patients requiring treatment due to its clinical efficacy and mostly tolerable side effects. However, it does not cure the disease, and patients must undergo prolonged periods of treatment. Christoph Bock and his group at CeMM investigated the molecular program with which CLL cells and other immune cells response to ibrutinib treatment in patients with CLL. Their goal was to learn the epigenetic and transcriptional patterns that predict how swiftly the treatment is having an effect on the CLL cells and how long it takes for the disease to respond in each individual patient.

In previous studies, scientists had investigated only specific aspects of the molecular response to ibrutinib, focusing largely on genetic drug resistance or the transcriptome response of cancer cells. For the first time, CeMM researchers provide a comprehensive genome-scale, time-resolved analysis of the regulatory response to this drug in primary patient samples. The authors used a combination of immunophenotyping, single-cell transcriptome profiling (scRNA-seq) and chromatin mapping (ATAC-seq) to jointly monitor the activity, regulation and expression of the CLL cells and other cell types of the immune system. Importantly, they performed this analysis at eight pre-defined time points during the ibrutinib therapy, following seven individual patients over a standardized 240-day period after the start of the treatment.

Through integrative bioinformatic analysis of the resulting dataset, the authors were able to describe at high resolution how ibrutinib induces a very consistent chain of events on cancer cells over time across all patients. They found that ibrutinib first acts right at the center of the CLL cells’ activity, causing the genes that establish the cancer cell identity of the CLL cells to shut down, and then puts them in a dormant state. This means that the cancer cells stop dividing but quiescently survive, waiting for the right environment conditions to begin proliferation once again.

The present study by André Rendeiro, Thomas Krausgruber and colleagues is the result of cross-disciplinary collaborations with researchers from the Department of Hematology and Stem Cell Transplantation of the National Institute of Hematology and Infectious Diseases at the Central Hospital of Southern Pest, and the Department of Pathology and Experimental Cancer Research of the Semmelweis University in Budapest (Hungary). It constitutes one of the first high-resolution, multi-omics time series of the molecular response to targeted therapy in cancer patients, and it establishes a broadly applicable approach for analyzing drug-induced regulatory programs, identifying molecular response markers for targeted therapy. Finally, the study could help stratify patients into fast and slow responders based on characteristic molecular markers and open up new directions for the development of ibrutinib-based combination therapies for CLL.

The study “Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in chronic lymphocytic leukemia” was published in Nature Communications on 29 January 2020 DOI: 10.1038/s41467-019-14081-6

Funding:The study was funded with support of a New Frontiers Group award of the Austrian Academy of Sciences and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No 679146, awarded to Christoph Bock). Thomas Krausgruber was supported by a Lise-Meitner fellowship from the Austrian Science Fund (FWF M2403). Nikolaus Fortelny was supported by a fellowship from the European Molecular Biology Organization (EMBO ALTF 241-2017). Donat Alpar and Csaba Bödör were supported by the K119950, KH17-126718, NVKP_16-1-2016-0004, and NVKP_16-1-2016-0005 grants of the Hungarian National Research, Development and Innovation Office, the Janos Bolyai research scholarship, and the LP95021 grant of the Hungarian Academy of Sciences. Christian Schmidl was supported by a Feodor Lynen Fellowship of the Alexander von Humboldt Foundation.

• Do you want to work in an environment that promotes free-minded scientific creativity, and translate your findings to impact medical practice and improve healthcare?• Are you excited to gain a new understanding of the molecular physiology and pathology of humans?• Do you want to join an international group of highly collaborative and successful colleagues that help you achieve your training and research goals?• Are you a person who enjoys teamwork across disciplines and within a broader cultural and social context?

The research areaThe 2020 CeMM PhD Program will focus on the thematic areas of Infection, Immunity, Metabolism, Cancer, Rare Diseases, Network Medicine, and Design Chemistry. These areas are built on the pillars of epigenetics and genome integrity, bioinformatics and systems biology, high-throughput genetics, genomics and proteomics, molecular and cell biology, chemical biology, and organic chemical synthesis.

The ProgramOur goal is to enable and empower students with the ability to successfully design, execute, manage and explain a research project in modern molecular medicine, through a strongly participatory and interactiveprogram. The program is conceptualized in three “modes”: collect, connect and contribute.These will guide you through scientific excellence in data generation and validation to responsible and professional scientific citizenship.

You are• An exceptionally motivated PhD candidate with a keen interest in interdisciplinary teamwork and science that nurtures the precise, personalized, preditive and preventive medicine of the future• Excellent in writing and speaking English• A candidate with (or will soon obtain) a final degree in medicine, biology, chemistry, bioinformatics, computer science, engineering, physics, mathematics or a similar subject (minimum requirement is a 4-year Bachelor's degree)

The host and partner institutesCeMM and LBI-RUD are partner institutes with identical principles of excellence, competitiveness, internationality, as well as mentoring and training, together with the Medical University of Vienna, and the Children’s Cancer Research Institute (CCRI) of the St. Anna Children’s Hospital they operate in a unique mode of super-cooperation. Here biology is connected with medicine, experiments with computation, discovery with translation, and science with society and the arts.

The mission of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an internationaland creative team of scientists and medical doctors pursues free-minded, basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM’s research is basedon post-genomic technologies and focuses on societally important diseases, such as immune disorders and infections, cancer and metabolic disorders. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future. CeMM is part of EU-LIFE an alliance of 13 top research centres in life sciences to support and strengthen European research excellence.

LBI-RUD, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases focuses its research on rare diseases of the immune system, hematopoiesis, and the nervous system. This research will not only provide the basis for targeted therapies, but also provide unique and novel insights into human biology far beyond the specific disease. LBI-RUD is highly connected in global networks promoting cooperation and synergy between different disciplines and engaging rare disease patients.

CeMM and LBI-RUD enjoy a privileged location right in the centre of the Medical Campus Vienna, one of the largest in Europe, door-to-door with the Medical University of Vienna and the Vienna General Hospital (AKH). The Medical University of Vienna is the largest medical research institution in Austria and the AKH is one of the largest hospitals in Europe treating several hundred thousand people a year. Close by, the Children’s Cancer Research Institute (CCRI) of the St. Anna Children’s Hospital work hard to develop new and improved treatment options for the 250-300 children and adolescents diagnosed with cancer each year in Austria.

The partner institutions, CeMM, LBI-RUD, CCRI and the Medical University of Vienna are located within walking distance of Vienna’s historical city centre. Vienna is repeatedly ranked as the world’s best city to live in and is a United Nations city with a large international, English- speaking community. The official language at CeMM is English, and more than 40 different nationalities are currently represented at the institutes.

From 15 to 17 January 2020, the Christian Doppler Laboratory Closing Symposium “From Understanding Chromatin Dynamics to Therapeutics Targeting” will take place at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna (Austria). The event is jointly organized by CeMM PI Stefan Kubicek, CeMM PostDoc Sandra Schick, and Senior Principle Scientist Simon Wöhrle (Boehringer Ingelheim). The highlight of the programme is the keynote lecture by Brian R. Cairns, Chair of the Oncological Sciences Department at the University of Utah School of Medicine, and an investigator with the Huntsman Cancer Institute (USA). The line-up of speakers also includes EMBO Members Tom Owen-Hughes (University of Dundee, UK) and Dirk Schübeler (FMI for Biomedical Research in Basel, Switzerland), among other excellent speakers from Austria, Germany, Switzerland, the United Kingdom and the United States.

The symposium is organized on the occasion of the ending of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, a close collaboration between Stefan Kubicek's Group at CeMM, Boehringer Ingelheim and Haplogen, to celebrate its successful outcome. The Christian Doppler Research Association promotes the cooperation between science and business. Under the direction of highly qualified scientists, research groups work in close contact with the commercial partners on innovative responses to business-related research questions.

For the past seven years, Stefan Kubicek’s Group has collaborated with industry on application-oriented basic research, which has resulted in 17 high-impact publications including the CD Lab as an affiliation, nine of them with Stefan Kubicek as a corresponding author. The key highlight was the study published last year in Nature Genetics with Sandra Schick as first author (“Systematic characterization of BAF mutations explains intra-complex synthetic lethalities in human cancers”. DOI: 10.1038/s41588-019-0477-9).

The CD Laboratory programme has funded a compact research group of 13 scientists over the past seven years, who have worked at CeMM, and are all still active in research. Some of them have moved to independent academic positions and others have also taken on leadership roles in industry. The CD Laboratory funding programme has supported the research of Stefan Kubicek’s Lab, resulting in an ERC Consolidator Grant “CHROMABOLISM” awarded in 2018, and has also laid the foundation for future research. We thank the Christian Doppler Research Association, Boehringer Ingelheim and Haplogen for this successful collaboration.

December 06, 2019

End of ERC Scientific Council Membership Giulio Superti-Furga

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Giulio Superti-Furga and Jean-Pierre Bourguignon at ERC Meeting in Brussels, December 2019

At the end of this year, Giulio Superti-Furga, Scientific Director of CeMM and Professor for Medical Systems Biology of the Medical University of Vienna, will terminate his appointment as Member of the Scientific Council of the European Research Council, which he started in January 2017. We thank Giulio for this important scientific community service during difficult political times, strongly advocating for the support of frontier research on new ideas, as the best means to reach innovation and economic welfare, and to sustain the ground for democracy. Having been awarded two ERC Advanced Investigator Grants in the past and two ERC Proof-of-Concept Grants to explore the application potential of research ideas, Giulio Superti-Furga, who also acted as ERC panel member, will continue to be a strong supporter of the ERC, which celebrated its 10th anniversary in 2017 and is now preparing for Horizon Europe.

Coinciding with this is the end of the function of ERC President Jean-Pierre Bourguignon, a renowned French mathematician, who has been highly successful at further increasing the prestige of the ERC and effectively safeguarding the budget. CeMM’s students, postdocs and faculty have a fond memory of his visit in Vienna in October 2017. As part of the scientific community, we thank Jean-Pierre Bourguignon for his inspiring leadership. From 2010 to 2013 Prof. Helga Nowotny, a Viennese Professor of Social Studies of Science, also held this prestigious position. We look forward to the term of the designated new President Mauro Ferrari, who will start in January 2020. We wish him success at leading the ERC in the future years.

The European Research Council is the most important and prestigious funding institution for basic research in any field conducted within the European Union. Excellence is the sole criterion for selection, there are neither thematic priorities, nor geographical or other quotas for funding. Perhaps the most important funding programme of the ERC is the ERC Starting Independent Research Grant, promoting early scientific independence of promising talents with 2 million euros over a period of 5 years. With its different programme,s it has created a very positive impact on the attractiveness of Europe as a research area.

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Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences identified a key mechanism for how antiviral immune responses reprogram liver metabolism. Their recent study, which was published in the renowned scientific journal Immunity, investigated the communication between inflammation and liver metabolism during chronic viral infection. Surprisingly, the antiviral cytokine type I interferon (IFN-I) was found to be a master regulator of metabolic pathways in liver cells. The researchers focused on the urea cycle, a central metabolic node, and found that it is disrupted by IFN-I during viral infection. This led to altered serum metabolite concentrations which regulated antiviral immunity and reduced liver pathology.

The liver is a crucial organ for systemic metabolism in our body. Apart from the turnover of biomolecules and drug metabolism, the liver’s main function is the removal of toxic substances from the organism. Hepatocytes, or liver cells, are the most abundant cell type and functional unit of the liver. They are metabolic powerhouses in the healthy organism, but they also serve as important immune signaling platforms during infections. As such, they have the potential to react to a range of cytokines – small molecules that are essential for the coordination of immune responses.

Previous studies in the field of immunology and metabolism, or immunometabolism, unveiled groundbreaking mechanisms about how cells of the immune system need to adjust their metabolism to perform their functions to fight pathogens and cancer. Building on this, Andreas Bergthaler and his group at CeMM aimed to study the immunometabolic changes that occur in the whole organism during infection. They particularly focused on the liver due to its important role in controlling systemic metabolism.

To dissect the involved complex processes, the authors took advantage of the benchmark model of chronic infection, the lymphocytic choriomeningitis virus (LCMV). Research with LCMV had already led to fundamental insights into immunology over the past 80 years, and notably contributed to three Nobel Prizes. Among them is the 2018 Nobel Prize in Physiology or Medicine, which was awarded to James Allison and Tasuku Honjo for their discoveries relating to the revolutionary new cancer immunotherapies which exploit the body’s own immune killer cells, or CD8 T cells.

The present study by Alexander Lercher, Anannya Bhattacharya et al. is the result of cross-disciplinary collaborations with researchers from the Medical University of Vienna and the University of Veterinary Medicine in Vienna (Austria), as well as from the Hannover Medical School (Germany), the Cantonal Hospital St. Gallen (Switzerland) and the company Bio-Cancer Treatment International Ltd (China). The study was designed as an integrative unbiased approach to investigate the molecular changes in the liver during chronic infection. Next to expected inflammatory changes, the authors identified intriguing changes in hepatocyte metabolism. Many central metabolic pathways, among them the urea cycle, were found to be repressed upon infection. The urea cycle is essential to remove toxic ammonia from the body to prevent brain damage. Surprisingly, the researchers identified the antiviral cytokine signaling pathway of type I interferons (IFN-I) as a regulator of the urea cycle. This resulted in altered blood concentrations of the amino acids arginine and ornithine. “A key experiment for us was that when we removed the receptor for IFN-I on the surface of hepatocytes, we didn’t see these metabolic changes anymore”, says Alexander Lercher, first author of the study and PhD student in the laboratory of CeMM Principal Investigator Andreas Bergthaler. The systemic changes of arginine and ornithine were found to inhibit antiviral CD8 T cell responses and to reduce liver damage.

One of the most important revelations of this study was the identification of IFN-I signaling as a master regulator for the repression of metabolic processes in hepatocytes upon infection. “We were really surprised that an antiviral molecule affects such vital biological processes as the urea cycle during infection”, says Michael Trauner, co-author of the study and head of the Department of Gastroenterology and Hepatology at the Medical University of Vienna. Together, these findings shed new light on how the body’s immune system evolved to regulate liver metabolism that modulate CD8 T cell responses and reduce collateral tissue damage during infection. Andreas Bergthaler: “We regard this study an important contribution to the field of systemic immunometabolism. It also highlights the central role of the liver for our immune system and how organs of the body communicate through metabolites.” In the future, such findings may be exploited to therapeutically intervene with the regulation of metabolic processes to modulate CD8 T cell responses in diverse diseases such as infection, cancer and autoimmunity.

The study “Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function” was published in Immunity on 26 November 2019.DOI: 10.1016/j.immuni.2019.10.014

Funding:The study was funded with support of the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No 677006, “CMIL” to Andreas Bergthaler). Alexander Lercher, Anannya Bhattacharya and Julia S. Brunner were supported by a DOC fellowship of the Austrian Academy of Sciences. Natalia Pikor was supported by an Ambizione grant awarded by the Swiss National Science Foundation (PZ00P3_180011/1).